CREB-binding protein (CBP) is a versatile histone acetyltransferase (HAT), which plays a crucial role in the regulation of pro-inflammatory cytokine gene transcription in inflammatory diseases including sepsis and lung disorders. Therefore, selectively modulating the availability of CBP can potentially suppress cytokine storm and lessen the severity of sepsis. The ubiquitin-proteasome system disposes of the vast majority of intracellular proteins, including CBP. Ubiquitination is a reversible reaction. De-ubiquitination i mediated by a group of de- ubiquitinating enzymes, which enhances protein stability by removing the degradation signal from the target proteins. However, the de-ubiquitination of CBP has not been previously investigated. Our preliminary data show that ubiquitin specific peptidase (USP)14 de-ubiquitinates CBP and enhances its stability, and that inhibition of USP14 attenuates LPS-increased CBP stability, histone acetylation, and cytokine release, thereby lessening both systemic and pulmonary inflammation. This is the first study to identify a de-ubiquitinating enzyme regulating stability and biological effects of a HAT. This study suggests that IU1, an inhibitor of USP14, is an anti-inflammatory small molecule potentially applicable in new medication for sepsis. Execution of these studies will lay the groundwork for a significant mechanistic advance for the molecular regulation of the innate immune response during severe infection.